Abstract
Purpose
To investigate the effect of dose level and anatomical site of injection on the pharmacokinetics of rituximab in mice, and to evaluate the utility of a pharmacokinetic model for describing interspecies differences in subcutaneous absorption between mice and rats.
Methods
Rituximab serum concentrations were measured following intravenous and subcutaneous administration at the back and abdomen of mice. Several approaches were compared for scaling model parameters from estimated values in rats.
Results
The bioavailability of rituximab following subcutaneous injection was inversely related to the dose level and was dependent on the site of injection in mice. The overall rate of absorption was faster in mice as compared to rats. Subcutaneous absorption profiles were well described using the proposed structural model, in which the total receptor concentration, the affinity of rituximab to the receptor, and the degradation rate constant were assumed to be species independent.
Conclusions
Subcutaneous absorption processes show similar trends in rats and mice, although the magnitude differs between species. A mathematical model that combines the absorption of free and bound antibody with presystemic degradation successfully captured rituximab pharmacokinetics in both species, and approaches for sharing and scaling parameters between species were identified.
Similar content being viewed by others
Abbreviations
- FcRn:
-
Neonatal Fc receptor
- IV:
-
Intravenous
- mAbs:
-
Monoclonal antibodies
- SC:
-
Subcutaneous
References
Richter WF, Bhansali SG, Morris ME. Mechanistic determinants of biotherapeutics absorption following SC administration. AAPS J. 2012;14(3):559–70.
Bittner B, Schmidt J. Subcutaneous administration of monoclonal antibodies in oncology as alternative to established intravenous infusion. Pharm Ind. 2012;74(4):638–43.
Aue G, Lindorfer MA, Beum PV, Pawluczkowycz AW, Vire B, Hughes T, et al. Fractionated subcutaneous rituximab is well-tolerated and preserves CD20 expression on tumor cells in patients with chronic lymphocytic leukemia. Haematologica. 2010;95(2):329–32.
Swartz MA. The physiology of the lymphatic system. Adv Drug Deliv Rev. 2001;50(1–2):3–20.
Porter CJ, Charman SA. Lymphatic transport of proteins after subcutaneous administration. J Pharm Sci. 2000;89(3):297–310.
Kagan L, Gershkovich P, Mendelman A, Amsili S, Ezov N, Hoffman A. The role of the lymphatic system in subcutaneous absorption of macromolecules in the rat model. Eur J Pharm Biopharm. 2007;67(3):759–65.
McDonald TA, Zepeda ML, Tomlinson MJ, Bee WH, Ivens IA. Subcutaneous administration of biotherapeutics: current experience in animal models. Curr Opin Mol Ther. 2010;12(4):461–70.
Deng R, Iyer S, Theil FP, Mortensen DL, Fielder PJ, Prabhu S. Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: What have we learned? MAbs. 2011;3(1):61–6.
Chen T, Mager DE, Kagan L. Interspecies modeling and prediction of human exenatide pharmacokinetics. Pharm Res. 2013;30(3):751–60.
Woo S, Jusko WJ. Interspecies comparisons of pharmacokinetics and pharmacodynamics of recombinant human erythropoietin. Drug Metab Dispos. 2007;35(9):1672–8.
Kagan L, Abraham AK, Harrold JM, Mager DE. Interspecies scaling of receptor-mediated pharmacokinetics and pharmacodynamics of type I interferons. Pharm Res. 2010;27(5):920–32.
Kagan L, Turner MR, Balu-Iyer SV, Mager DE. Subcutaneous absorption of monoclonal antibodies: role of dose, site of injection, and injection volume on rituximab pharmacokinetics in rats. Pharm Res. 2012;29(2):490–9.
Kagan L, Mager DE. Mechanisms of subcutaneous absorption of rituximab in rats. Drug Metab Dispos. 2013;41(1):248–55.
Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548–58.
Deng R, Meng YG, Hoyte K, Lutman J, Lu Y, Iyer S, et al. Subcutaneous bioavailability of therapeutic antibodies as a function of FcRn binding affinity in mice. MAbs. 2012;4(1):101–9.
Kota J, Machavaram KK, McLennan DN, Edwards GA, Porter CJ, Charman SA. Lymphatic absorption of subcutaneously administered proteins: influence of different injection sites on the absorption of darbepoetin alfa using a sheep model. Drug Metab Dispos. 2007;35(12):2211–7.
Beshyah SA, Anyaoku V, Niththyananthan R, Sharp P, Johnston DG. The effect of subcutaneous injection site on absorption of human growth hormone: abdomen versus thigh. Clin Endocrinol (Oxford). 1991;35(5):409–12.
Macdougall IC, Jones JM, Robinson MI, Miles JB, Coles GA, Williams JD. Subcutaneous erythropoietin therapy: comparison of three different sites of injection. Contrib Nephrol. 1991;88:152–6. discussion 7–8.
Kagan L, Gershkovich P, Wasan KM, Mager DE. Dual physiologically based pharmacokinetic model of liposomal and nonliposomal amphotericin B disposition. Pharm Res. 2014;31(1):35–45.
Mager DE. Target-mediated drug disposition and dynamics. Biochem Pharmacol. 2006;72(1):1–10.
Hansen RJ, Balthasar JP. Pharmacokinetic/pharmacodynamic modeling of the effects of intravenous immunoglobulin on the disposition of antiplatelet antibodies in a rat model of immune thrombocytopenia. J Pharm Sci. 2003;92(6):1206–15.
Dong JQ, Salinger DH, Endres CJ, Gibbs JP, Hsu CP, Stouch BJ, et al. Quantitative prediction of human pharmacokinetics for monoclonal antibodies: retrospective analysis of monkey as a single species for first-in-human prediction. Clin Pharmacokinet. 2011;50(2):131–42.
Wang W, Prueksaritanont T. Prediction of human clearance of therapeutic proteins: simple allometric scaling method revisited. Biopharm Drug Dispos. 2010;31(4):253–63.
Jolling K, Perez Ruixo JJ, Hemeryck A, Vermeulen A, Greway T. Mixed-effects modelling of the interspecies pharmacokinetic scaling of pegylated human erythropoietin. Eur J Pharm Sci. 2005;24(5):465–75.
Mager DE, Neuteboom B, Efthymiopoulos C, Munafo A, Jusko WJ. Receptor-mediated pharmacokinetics and pharmacodynamics of interferon-beta1a in monkeys. J Pharmacol Exp Ther. 2003;306(1):262–70.
Gao W, Jusko WJ. Target-mediated pharmacokinetic and pharmacodynamic model of exendin-4 in rats, monkeys, and humans. Drug Metab Dispos. 2012;40(5):990–7.
Rath T, Kuo TT, Baker K, Qiao SW, Kobayashi K, Yoshida M, et al. The immunologic functions of the neonatal Fc receptor for IgG. J Clin Immunol. 2013;33 Suppl 1:S9–17.
Salar A, Bouabdallah R, McIntyre C, Sayyed P, Bittner B. A two-stage phase Ib stufy to investigate the pharmacokinetics, safety and tolerability of subcutaneous rituximab in patients with follicular lymphoma as part of maintenance treatment. 53rd American Society of Hematology Annual Meeting and Exposition; December 10–13, 2011; San Diego, CA, 2010.
Assouline S, Buccheri V, Delmer A, Doelken G, Gaidano G, McIntyre C, et al. Subcutaneous rituximab in combination with fludarabine and cyclophosphamide for patients with CLL: initial results of a phase Ib study (SAWYER [BO25341]) show non-inferior pharmacokinetics and comparable safety to that of intravenous rituximab. 54th American Society of Hematology Annual Meeting and Exposition; December 8–11, 2012; Atlanta, GA, 2012.
ACKNOWLEDGMENTS AND DISCLOSURES
This work was supported, in part, by the Center for Protein Therapeutics, University at Buffalo, State University of New York.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kagan, L., Zhao, J. & Mager, D.E. Interspecies Pharmacokinetic Modeling of Subcutaneous Absorption of Rituximab in Mice and Rats. Pharm Res 31, 3265–3273 (2014). https://doi.org/10.1007/s11095-014-1416-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-014-1416-1